NM_003640.5:c.934G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003640.5(ELP1):c.934G>A(p.Glu312Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0221 in 1,613,956 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 43 hom., cov: 33)

Exomes 𝑓: 0.022 ( 435 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.65

Variant links:

Genes affected

ELP1 (HGNC:5959): (elongator acetyltransferase complex subunit 1) The protein encoded by this gene is a scaffold protein and a regulator for three different kinases involved in proinflammatory signaling. The encoded protein can bind NF-kappa-B-inducing kinase and I-kappa-B kinases through separate domains and assemble them into an active kinase complex. Mutations in this gene have been associated with familial dysautonomia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ELP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025151968).

BP6

Variant 9-108916228-C-T is Benign according to our data. Variant chr9-108916228-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108916228-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0211 (3212/152316) while in subpopulation NFE AF= 0.0247 (1678/68028). AF 95% confidence interval is 0.0237. There are 43 homozygotes in gnomad4. There are 1576 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5 link	c.934G>A	p.Glu312Lys	missense_variant	Exon 10 of 37	ENST00000374647.10	NP_003631.2	O95163Q4LE38Q8N516
ELP1	NM_001318360.2 link	c.592G>A	p.Glu198Lys	missense_variant	Exon 10 of 37		NP_001305289.1	O95163A0A6Q8PGW3B4E3I9
ELP1	XM_047423991.1 link	c.934G>A	p.Glu312Lys	missense_variant	Exon 10 of 25		XP_047279947.1
ELP1	NM_001330749.2 link	c.-114G>A		5_prime_UTR_variant	Exon 8 of 35		NP_001317678.1	F5H2T0B3KNB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.934G>A	p.Glu312Lys	missense_variant	Exon 10 of 37	1	NM_003640.5	ENSP00000363779.5		O95163

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3200

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0247

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0189

AC:

4765

AN:

251452

Hom.:

AF XY:

0.0192

AC XY:

2603

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0223

Gnomad AMR exome

AF:

0.00737

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00715

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0223

AC:

32522

AN:

1461640

Hom.:

435

Cov.:

AF XY:

0.0215

AC XY:

15645

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0214

Gnomad4 AMR exome

AF:

0.00740

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00750

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.0252

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0211

AC:

3212

AN:

152316

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1576

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0226

Gnomad4 AMR

AF:

0.0136

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00829

Gnomad4 FIN

AF:

0.0238

Gnomad4 NFE

AF:

0.0247

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0230

Hom.:

Bravo

AF:

0.0200

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.0211

AC:

ESP6500EA

AF:

0.0226

AC:

194

ExAC

AF:

0.0204

AC:

2483

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0240

EpiControl

AF:

0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial dysautonomia

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Apr 03, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.69

REVEL

Benign

0.048

Sift

Benign

0.36

Sift4G

Benign

0.50

Polyphen

0.075

Vest4

0.050

MPC

0.10

ClinPred

0.016

GERP RS

4.7

Varity_R

0.046

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over